Improvement of cognitive function in Alzheimer's disease model mice by genetic and pharmacological inhibition of the EP ₄ receptor

Amyloid-β peptide (Aβ), which is generated by the β- and γ-secretase-mediated proteolysis of β-amyloid precursor protein (APP), plays an important role in the pathogenesis of Alzheimer's disease (AD). We recently reported that prostaglandin E ₂ (PGE ₂) stimulates the production of Aβ through both EP ₂ and EP ₄ receptors and that activation of the EP ₄ receptor stimulates Aβ production through endocytosis and activation of γ-secretase. We here found that transgenic mice expressing mutant APP (APP23) mice showed a greater or lesser apparent cognitive deficit when they were crossed with mice lacking EP ₂ or EP ₄ receptors, respectively. Mice lacking the EP ₄ receptor also displayed lower levels of Aβ plaque deposition and less neuronal and synaptic loss than control mice. Oral administration of a specific EP ₄ receptor antagonist, AE3-208 to APP23 mice, improved their cognitive performance, as well as decreasing brain levels of Aβ and suppressing endocytosis and activation of γ-secretase. Taken together, these results suggest that inhibition of the EP ₄ receptor improves the cognitive function of APP23 mice by suppressing Aβ production and reducing neuronal and synaptic loss. We therefore propose that EP ₄ receptor antagonists, such as AE3-208, could be therapeutically beneficial for the prevention and treatment of AD.